Micafungin is a novel anti-fungal drug of pneumocandins, and it inhibits the synthesis of a fungi cell wall component, i.e. β-1,3-D-glucan synthase, whereby destroying the structure of fungal cells and thus leading to cytolysis. Micafungin is widely used for treating various infections, such as infections caused by Aspergillus, Candida, Cryptococcus, Mucor, Actinomyces, Histoplasma, Dermatophytes and Fusarium and the like.
Micafungin Sodium (also named as FK463) is the active pharmaceutical ingredient of the marketed drug, Mycamine. The chemical structure of micafungin Sodium is shown as follows:

5-[(1S,2S)-2-[(3S,6S,9S,11R,15S,18S,20R,21R,24S,25S,26S)-3-[(R)-2-carbamoyl-1-hy droxyethyl]-11,20,21,25-tetrahydroxy-15-[(R)-1-hydroxyethyl]-26-methyl-2,5,8,14,17,23-hexaoxo-18-[4-[5-(4-pentoxyphenyl)isoxazol-3-yl]benzoylamino]-1,4,7,13,16,22-hex aazatricyclo[22.3.0.0.09,13]heptacosan-6-yl]-1,2-dihydroxyethyl]-2-hydroxy phenyl sulfate.
The compound of formula I is a polypeptide compound with poor stability, and its quality and efficacy are affected by degradation products generated during transportation or long-term storage. Furthermore, the compound of formula I is difficult to be crystallized and generally it is in an amorphous state.
U.S. Pat. Nos. 6,107,458 and 7,199,248 and WO 96/111210 disclosed methods for preparing and purifying the compounds of Formula I. Wherein, in U.S. Pat. No. 7,199,248, Micafungin DIPEA (diisopropylethylamine) salt was purified through filtration and chromatographic separation, and then precipitated with acetone and ethyl acetate to give the amorphous form of the compound of formula I.
Atsushi Ohigashi et al., “Process Development of Micafungin, a Novel Lipopeptide Antifungal Agent”, Journal of Synthesis Organic Chemistry, 2006, Vol 64, (12), described that the compound of formula I can be precipitated by adding a mixture of acetone and ethyl acetate to the elution solution of the compound of formula I from ion exchange, so as to give the amorphous compound of formula I. Before drying, the content of solvent in the precipitate of the compound of formula I was high (Dry/Wet=0.25), and the precipitate of the compound of formula I contained about 75% of solvent. To reduce the content of solvent to below the standard value, the drying time has to be extended, which, however, will cause an increase in the degradation products of the compound of formula I and a reduction in quality.
In addition, the patent application WO 03/018615 of Fujisawa Pharmaceutical Co., Ltd. disclosed a new crystal form of the compound of the formula I and a preparation method thereof. In WO03/018615, the compound of formula I in amorphous form was dissolved in an aqueous alcohol solution or aqueous acetone solution, and a solvent, such as ethyl acetate, methylene chloride, acetone and acetonitrile was added, so as to give the B82-type acicular crystals of the compound of formula I. The crystal was obtained in an organic solvent, has a needle shape under microscope, and has peaks at the following 2θ angles in the X-ray powder diffraction pattern: 4.6°, 5.5°, 9.0°, 9.8°, 16.9°.
In “Study of Industrial Manufacturing Methods for Micafungin (FK463)”, Seihutsu kogaku Kaishi, 2005, Vol 83, YAMASHITA et al., from Fujisawa Pharmaceutical Co., Ltd., mentioned that needle-like crystals of FK463 were successfully obtained through optimization of solvent and control of pH. However, no specific embodiments and crystal data were disclosed. Since the prior patent application WO03/018615 of the company disclosed the B82-type needle-like crystals of the compounds of formula I, it can be seen that what YAMASHITA et al. obtained was also the B82-type needle-like crystal.
The present inventors prepared the B82-type acicular crystal according to the method of Example 1 in WO03/018615, and the resultant crystal was observed with an optical microscope, which reveals that the crystal is about 1 μm in size and has a fine-needle shape; d50 of the obtained crystals was determined as 0.2-1.0 um by Malven particle size analyzer. When the crystals were subjected to subsequent processing steps, such as filtration, drying or the like, the present inventors found that, because the B82-type crystals essentially have a fine-needle morphology, it is difficult to filter the crystals of the compound of formula I and the operation needs a long time. Before drying of the crystals, the content of solvent in the compound of formula I (Dry/Wet) was about 0.25, and a large amount of organic solvent was trapped in the crystal. To render the content of solvent in compliance with the requirements for active pharmaceutical ingredients (API), the drying temperature or the drying time has to be increased during the drying process. Such drying process, however, will increase the degradation product of the compound of formula I, seriously affecting the quality and stability of API. Upon study on the dried crystalline powder obtained from the needle-like crystal of B82 type, the inventors found that the bulk density of the needle-like crystal of B82 type is about 0.8 g/mL, which is relatively dense and unfavorable to the volatilization of solvents during the drying process of the crystalline powder, and thus directly affects the drying process; furthermore, when exposed to the environment, the crystal of B82 type is inclined to absorb moisture and has poor stability.
Therefore, there is an urgent need in the art to obtain a stable form of the compounds of formula I with regular morphology and lower bulk density, which can be easily filtered and dried, thereby achieving better commercial production.